In the wake of antimicrobial resistance and the severe lack of new antibiotics being discovered, researchers have turned to alternative strategies.
Antimicrobial peptides (AMPs) are a part of nature’s own defenses against bacterial infections. These peptides are small proteins that can create pores in the bacterial membrane or enter the cell and interfere with essential cellular processes. They are generally produced at the site of infection and act locally.
AMPs are produced by all virtually all living organisms, from mould to man, and many of these are structurally similar in many different species. In humans, they are a part of the innate immune system, the first line of defense against infections. The innate immune system responds to threats immediately and non-specifically. The second line of defense is the adaptive immune system, which involves production of specific antibodies and requires a few days to mount a full-scale response.
Challenges for antimicrobial peptides as therapy
Unfortunately, creating therapies with AMPs is not unproblematic due to their peptide nature. In general, peptide drugs must be given either by injection or directly into the affected tissue. AMPs are no exception to this rule.
Peptides only survive a few hours in the body and also penetrate poorly into tissues. Taken as pills, peptides are broken down in the small intestine and do not enter the blood stream. This makes achieving sufficient amounts of a peptide drug for longer periods of time very difficult and it may be necessary to give several injections or infusions per day. Topical administration is easier, and thus therapies like applying AMP-rich honey on severe burns have been tried more extensively.
It is generally believed that resistance to AMPs is more difficult to acquire for bacteria for at least two reasons:
- AMPs kill bacteria rapidly, leaving little time for adaption for the bug
- AMPs have multiple targets in the bacteria, so even if one target is altered, other targets are still available
Resistance development in new experiments
In a paper published in January 2017, researchers challenged this belief. They cultured strains of Staphylococcus aureus (MRSA) in conditions that resemble the conditions in the human body better than normal laboratory conditions. The bacteria were exposed to four different AMPs from different sources (plant, human, pig), for a total of seven days. The concentration of AMP was selected to be 30% of killing activity for the first 3-4 days, after which the concentration was increased by 50% for the next 3-4 days.
Within that week of experiment, several varieties of bacteria resistant to the AMPs emerged. Later analyses showed a multitude of genetic changes, which also lead to resistance to other AMPs as well as antibiotics. The changes were stable, meaning that the resistance was maintained even in the absence of AMPs. Furthermore, the modification did not change either the growth rate of the bacteria or its capability to cause disease, virulence.
Is resistance inevitable?
The experiment could be criticized for its setup – the selection of AMP concentration and use of only one or two peptides at a time. This kind of setup is more optimized for selecting resistance than to reflect the conditions during infection, but it does highlight an important process. In real life, the development of resistance is probably slower but still as relentless. If AMPs are misused in the same way as antibiotics have been, resistance is inevitable.
Importantly, given the structural likeness of AMPs across the whole tree of life, resistance to one peptide is likely to cause resistance others as well, so called cross-resistance. Resistance to an AMP or AMP-like drug may not only contribute to increasing multi-resistance but also disarm the human immune system. This would have devastating consequences for anyone who encounters these bacteria.
Kubicek-Sutherland JZ, Lofton H, Vestergaard M, Hjort K, Ingmer H, Andersson DI. “Antimicrobial peptide exposure selects for Staphylococcus aureus resistance to human defence peptides.” Journal of Antimicrobial Chemotherapy 2017 Jan;72(1):115-127